Emphysema is a common form of chronic obstructive pulmonary disease (COPD) that affects between 1.5 and 2 million Americans, and 3 to 4 times that number of patients worldwide. [American Thoracic Society Consensus Committee “Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease,” Am. J. Resp. Crit. Care Med. 1995, 152, 78-83; and Pauwels, R., et al. “Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease,” Am. J. Resp. Crit. Care Med. 2001, 163, 1256-1271.] It is characterized by destruction of the small airways and lung parenchyma due to the release of enzymes from inflammatory cells in response to inhaled toxins. [Stockley, R. “Neutrophils and protease/antiprotease imbalance,” Am. J. Resp. Crit. Care Med. 1999, 160, S49-S52.] Although this inflammatory process is usually initiated by cigarette smoking, once emphysema reaches an advanced stage, it tends to progress in an unrelenting fashion, even in the absence of continued smoking [Rutgers, S. R., et al. “Ongoing airway inflammation inpatients with COPD who do not currently smoke,” Thorax 2000, 55, 12-18.]
The class of enzymes that are responsible for producing tissue damage in emphysema are known as proteases. These enzymes are synthesized by inflammatory cells within the body and when released, they act to degrade the collagen and elastin fibers which provide mechanical integrity and elasticity to the lung. [Jeffery, P. “Structural and inflammatory changes in COPD: a comparison with asthma,” Thorax 1998, 53, 129-136.] The structural changes that result from the action of these enzymes are irreversible, cumulative, and are associated with loss of lung function that eventually leaves patients with limited respiratory reserve and reduced functional capacity. [Spencer, S. et al. “Health status deterioration inpatients with chronic obstructive pulmonary disease,” Am. J. Resp. Crit. Care Med. 2001, 163, 122-128; and Moy, M. L., et al. “Health-related quality of life improves following pulmonary rehabilitation and lung volume reduction surgery,” Chest 1999, 115, 383-389.]
In contrast to other common forms of COPD, such as asthma and chronic bronchitis for which effective medical treatments exist, conventional medical treatment is of limited value in patients with emphysema. Although emphysema, asthma, and chronic bronchitis each cause chronic airflow obstruction, limit exercise capacity, and cause shortness of breath, the site and nature of the abnormalities in asthma and chronic bronchitis are fundamentally different from those of emphysema. In asthma and chronic bronchitis, airflow limitation is caused by airway narrowing due to smooth muscle constriction and mucus hyper-secretion. Pharmacologic agents that relax airway smooth muscle and loosen accumulated secretions are effective at improving breathing function and relieving symptoms. Agents that act in this way include beta-agonist and anti-cholinergic inhalers, oral theophylline preparations, leukotriene antagonists, steroids, and mucolytic drugs.
In contrast, airflow limitation in emphysema is not primarily due to airway narrowing or obstruction, but due to loss of elastic recoil pressure as a consequence of tissue destruction. Loss of recoil pressure compromises the ability to fully exhale, and leads to hyper-inflation and gas trapping. Although bronchodilators, anti-inflammatory agents, and mucolytic agents are frequently prescribed for patients with emphysema, they are generally of limited utility since they are intended primarily for obstruction caused by airway disease; these classes of compounds do nothing to address the loss of elastic recoil that is principally responsible for airflow limitation in emphysema. [Barnes, P. “Chronic Obstructive Pulmonary Disease,” N. Engl. J. Med. 2000, 343(4), 269-280.]
While pharmacologic treatments for advanced emphysema have been disappointing, a non-medical treatment of emphysema has recently emerged, which has demonstrated clinical efficacy. This treatment is lung volume reduction surgery (LVRS). [Flaherty, K. R. and F J. Martinez “Lung volume reduction surgery for emphysema,” Clin. Chest Med. 2000, 21(4), 819-48.]
LVRS was originally proposed in the late 1950s by Dr. Otto Brantigan as a surgical remedy for emphysema. The concept arose from clinical observations which suggested that in emphysema the lung was “too large” for the rigid chest cavity, and that resection of lung tissue represented the best method of treatment since it would reduce lung size, allowing it to fit and function better within the chest. Initial experiences with LVRS confirmed that many patients benefited symptomatically and functionally from the procedure. Unfortunately, failure to provide objective outcome measures of improvement, coupled with a 16% operative mortality, led to the initial abandonment of LVRS.
LVRS was accepted for general clinical application in 1994 through the efforts of Dr. Joel Cooper, who applied more stringent pre-operative evaluation criteria and modern post-operative management schemes to emphysema patients. [Cooper, J. D., et al. “Bilateral pneumonectomy for chorale obstructive pulmonary disease,” J. Thorac. Cardiovasc. Surg. 1995, 109, 106-119.] Cooper reported dramatic improvements in lung function and exercise capacity in a cohort of 20 patients with advanced emphysema who had undergone LVRS. There were no deaths at 90-day follow-up, and physiological and functional improvements were markedly better than had been achieved with medical therapy alone.
While less dramatic benefits have been reported by most other centers, LVRS has nevertheless proven to be effective for improving respiratory function and exercise capacity, relieving disabling symptoms of dyspnea, and improving quality of life in patients with advanced emphysema. [Gelb, A. F., et al. “Mechanism of short-term improvement in lung function after emphysema resection,” Am. J. Respir. Crit. Care Med. 1996, 154, 945-51; Gelb, A. F., et al. “Serial lung function and elastic recoil 2 years after lung volume reduction surgery for emphysema,” Chest 1998, 113(6), 1497-506; Criner, G. and G. E. D'Alonzo, Jr., “Lung volume reduction surgery: finding its role in the treatment of patients with severe COPD,” J. Am. Osteopath. Assoc. 1998, 98(7), 371; Brenner, M., et al. “Lung volume reduction surgery for emphysema,” Chest 1996, 110(1), 205-18; and Ingenito, E. P., et al. “Relationship between preoperative inspiratory lung resistance and the outcome of lung-volume-reduction surgery for emphysema,” N. Engl. J. Med. 1998, 338, 1181-1185.] The benefits of volume reduction have been confirmed in numerous cohort studies, several recently-completed small randomized clinical trials, and the National Emphysema Treatment Trial (NETT). [Goodnight-White, S., et al. “Prospective randomized controlled trial comparing bilateral volume reduction surgery to medical therapy alone inpatients with severe emphysema,” Chest 2000, 118(Suppl 4), 1028; Geddes, D., et al. “L-effects of lung volume reduction surgery inpatients with emphysema,” N. Eng. J. Med. 2000, 343, 239-245; Pompeo, E., et al. “Reduction pneumoplasty versus respiratory rehabilitation in severe emphysema: a randomized study,” Ann. Thorac. Surg. 2000, 2000(70), 948-954; and Fishman, A., et al. “A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema,” N. Eng. J. Med. 2003, 348(21): 2059-73.] On average, 75-80% of patients have experienced a beneficial clinical response to LVRS (generally defined as a 12% or greater improvement in FEV, at 3 month follow-up). The peak responses generally occur at between 3 and 6 months post-operatively, and improvement has lasted several years. [Cooper, J. D. and S. S. Lefrak “Lung-reduction surgery: 5 years on,” Lancet 1999, 353(Suppl 1), 26-27; and Gelb, A. F., et al. “Lung function 4 years after lung volume reduction surgery for emphysema,” Chest 1999, 116(6), 1608-15.] Results from NETT have further shown that in a subset of patients with emphysema, specifically those with upper lobe disease and reduced exercise capacity, mortality at 29 months is reduced.
Collectively, these data indicate that LVRS improves quality of life and exercise capacity in many patients, and reduces mortality in a smaller fraction of patients, with advanced emphysema. Unfortunately, NETT also demonstrated that the procedure is very expensive when considered in terms of Quality Adjusted Life Year outcomes, and confirmed that LVRS is associated with a 5-6% 90 day mortality. [Chatila, W., S. Furukawa, and G. J. Criner, “Acute respiratory failure after lung volume reduction surgery,” Am. J. Respir. Crit. Care Med. 2000, 162, 1292-6; Cordova, F. C. and G. J. Criner, “Surgery for chronic obstructive pulmonary disease: the place for lung volume reduction and transplantation,” Curr. Opin. Pulm. Med. 2001, 7(2), 93-104; Swanson, S. J., et al. “No-cut thoracoscopic lung placation: a new technique for lung volume reduction surgery,” J. Am. Coll. Surg. 1997, 185(1), 25-32; Sema, D. L., et al. “Survival after unilateral versus bilateral lung volume reduction surgery for emphysema,” J. Thorac. Cardiovasc. Surg. 1999, 118(6), 1101-9; and Fishman, A., et al. “A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema,” N. Engl. J. Med. 2003, 348(21), 2059-73.] In addition, morbidity following LVRS is common (40-50%) and includes a high incidence of prolonged post-operative air-leaks, respiratory failure, pneumonia, cardiac arrhythmias, and gastrointestinal complications. Less invasive and less expensive alternatives that could produce the same physiological effect are desirable.
A hydrogel-based system for achieving lung volume reduction has been developed and tested, and its effectiveness confirmed in both healthy sheep, and sheep with experimental emphysema. [Ingenito, E. P., et al. “Bronchoscopic Lung Volume Reduction Using Tissue Engineering Principles,” Am. J. Respir. Crit. Care Med. 2003, 167, 771-778.] This system uses a rapidly-polymerizing, fibrin-based hydrogel that can be delivered through a dual lumen catheter into the lung using a bronchoscope. The fibrin-based system effectively blocks collateral ventilation, inhibits surfactant function to promote collapse, and initiates a remodeling process that proceeds over a 4-6 week period. Treatment results in consistent, effective lung volume reduction. These studies have confirmed the safety and effectiveness of using fibrin-based hydrogels in the lung to achieve volume reduction therapy.
While the above-mentioned studies confirmed the efficacy of a fibrin-based system for lung volume reduction, the system is complex, comprising more than 5 different components, and fibrinogen and thrombin are blood-derived. Further, the potential patient population is so large that wide-spread use could consume all of the fibrinogen produced worldwide. Moreover, because the product is derived from blood, contamination with blood-borne pathogens is always a concern. Lastly, fibrinogen-based systems are expensive. Accordingly, there is a need to develop a less-expensive system for lung volume reduction based on synthetic polymers.